Length of variable numbers of tandem repeats in the carboxyl ester lipase (CEL) gene may confer susceptibility to alcoholic liver cirrhosis but not alcoholic chronic pancreatitis

Karianne Fjeld; Sebastian Beer; Marianne Johnstone; Constantin Zimmer; Joachim Mössner; Claudia Ruffert; Mario Krehan; Christian Zapf; Pål Rasmus Njølstad; Stefan Johansson; Peter Bugert; Fabio Miyajima; Triantafillos Liloglou; Laura J Brown; Simon A Winn; Kelly Davies; Diane Latawiec; Bridget K Gunson; David N Criddle; Munir Pirmohamed; Robert Grützmann; Patrick Michl; William Greenhalf; Anders Molven; Robert Sutton; Jonas Rosendahl

doi:10.1371/journal.pone.0165567

Length of variable numbers of tandem repeats in the carboxyl ester lipase (CEL) gene may confer susceptibility to alcoholic liver cirrhosis but not alcoholic chronic pancreatitis

Karianne Fjeld, Sebastian Beer, Marianne Johnstone, Constantin Zimmer, Joachim Mössner, Claudia Ruffert, Mario Krehan, Christian Zapf, Pål Rasmus Njølstad, Stefan Johansson, Peter Bugert, Fabio Miyajima, Triantafillos Liloglou, Laura J Brown, Simon A Winn, Kelly Davies, Diane Latawiec, Bridget K Gunson, David N Criddle, Munir PirmohamedRobert Grützmann, Patrick Michl, William Greenhalf, Anders Molven, Robert Sutton, Jonas Rosendahl

Immunology and Immunotherapy

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Abstract

BACKGROUND: Carboxyl-ester lipase (CEL) contributes to fatty acid ethyl ester metabolism, which is implicated in alcoholic pancreatitis. The CEL gene harbours a variable number of tandem repeats (VNTR) region in exon 11. Variation in this VNTR has been linked to monogenic pancreatic disease, while conflicting results were reported for chronic pancreatitis (CP). Here, we aimed to investigate a potential association of CEL VNTR lengths with alcoholic CP.

METHODS: Overall, 395 alcoholic CP patients, 218 patients with alcoholic liver cirrhosis (ALC) serving as controls with a comparable amount of alcohol consumed, and 327 healthy controls from Germany and the United Kingdom (UK) were analysed by determination of fragment lengths by capillary electrophoresis. Allele frequencies and genotypes of different VNTR categories were compared between the groups.

RESULTS: Twelve repeats were overrepresented in UK ACP patients (P = 0.04) compared to controls, whereas twelve repeats were enriched in German ALC compared to alcoholic CP patients (P = 0.03). Frequencies of CEL VNTR lengths of 14 and 15 repeats differed between German ALC patients and healthy controls (P = 0.03 and 0.008, respectively). However, in the genotype and pooled analysis of VNTR lengths no statistical significant association was depicted. Additionally, the 16-16 genotype as well as 16 repeats were more frequent in UK ALC than in alcoholic CP patients (P = 0.034 and 0.02, respectively). In all other calculations, including pooled German and UK data, allele frequencies and genotype distributions did not differ significantly between patients and controls or between alcoholic CP and ALC.

CONCLUSIONS: We did not obtain evidence that CEL VNTR lengths are associated with alcoholic CP. However, our results suggest that CEL VNTR lengths might associate with ALC, a finding that needs to be clarified in larger cohorts.

Original language	English
Pages (from-to)	e0165567
Journal	PLoS ONE
Volume	11
Issue number	11
DOIs	https://doi.org/10.1371/journal.pone.0165567
Publication status	Published - 1 Nov 2016

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10.1371/journal.pone.0165567Licence: Creative Commons: Attribution (CC BY)

Fjeld_et_al_Length_of_variable_numbers_PLOS_One_2016
Checked for eligibility: 18/01/2017 Fjeld K, Beer S, Johnstone M, Zimmer C, Mossner J, Ruffert C, et al. (2016) Length of Variable Numbers of Tandem Repeats in the Carboxyl Ester Lipase (CEL) Gene May Confer Susceptibility to Alcoholic Liver Cirrhosis but Not Alcoholic Chronic Pancreatitis. PLoS ONE 11(11): e0165567. doi:10.1371/journal.pone.0165567
Final published version, 1.49 MBLicence: Creative Commons: Attribution (CC BY)

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Fjeld, K., Beer, S., Johnstone, M., Zimmer, C., Mössner, J., Ruffert, C., Krehan, M., Zapf, C., Njølstad, P. R., Johansson, S., Bugert, P., Miyajima, F., Liloglou, T., Brown, L. J., Winn, S. A., Davies, K., Latawiec, D., Gunson, B. K., Criddle, D. N., ... Rosendahl, J. (2016). Length of variable numbers of tandem repeats in the carboxyl ester lipase (CEL) gene may confer susceptibility to alcoholic liver cirrhosis but not alcoholic chronic pancreatitis. PLoS ONE, 11(11), e0165567. https://doi.org/10.1371/journal.pone.0165567

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title = "Length of variable numbers of tandem repeats in the carboxyl ester lipase (CEL) gene may confer susceptibility to alcoholic liver cirrhosis but not alcoholic chronic pancreatitis",

abstract = "BACKGROUND: Carboxyl-ester lipase (CEL) contributes to fatty acid ethyl ester metabolism, which is implicated in alcoholic pancreatitis. The CEL gene harbours a variable number of tandem repeats (VNTR) region in exon 11. Variation in this VNTR has been linked to monogenic pancreatic disease, while conflicting results were reported for chronic pancreatitis (CP). Here, we aimed to investigate a potential association of CEL VNTR lengths with alcoholic CP.METHODS: Overall, 395 alcoholic CP patients, 218 patients with alcoholic liver cirrhosis (ALC) serving as controls with a comparable amount of alcohol consumed, and 327 healthy controls from Germany and the United Kingdom (UK) were analysed by determination of fragment lengths by capillary electrophoresis. Allele frequencies and genotypes of different VNTR categories were compared between the groups.RESULTS: Twelve repeats were overrepresented in UK ACP patients (P = 0.04) compared to controls, whereas twelve repeats were enriched in German ALC compared to alcoholic CP patients (P = 0.03). Frequencies of CEL VNTR lengths of 14 and 15 repeats differed between German ALC patients and healthy controls (P = 0.03 and 0.008, respectively). However, in the genotype and pooled analysis of VNTR lengths no statistical significant association was depicted. Additionally, the 16-16 genotype as well as 16 repeats were more frequent in UK ALC than in alcoholic CP patients (P = 0.034 and 0.02, respectively). In all other calculations, including pooled German and UK data, allele frequencies and genotype distributions did not differ significantly between patients and controls or between alcoholic CP and ALC.CONCLUSIONS: We did not obtain evidence that CEL VNTR lengths are associated with alcoholic CP. However, our results suggest that CEL VNTR lengths might associate with ALC, a finding that needs to be clarified in larger cohorts.",

author = "Karianne Fjeld and Sebastian Beer and Marianne Johnstone and Constantin Zimmer and Joachim M{\"o}ssner and Claudia Ruffert and Mario Krehan and Christian Zapf and Nj{\o}lstad, {P{\aa}l Rasmus} and Stefan Johansson and Peter Bugert and Fabio Miyajima and Triantafillos Liloglou and Brown, {Laura J} and Winn, {Simon A} and Kelly Davies and Diane Latawiec and Gunson, {Bridget K} and Criddle, {David N} and Munir Pirmohamed and Robert Gr{\"u}tzmann and Patrick Michl and William Greenhalf and Anders Molven and Robert Sutton and Jonas Rosendahl",

year = "2016",

month = nov,

day = "1",

doi = "10.1371/journal.pone.0165567",

language = "English",

volume = "11",

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Fjeld, K, Beer, S, Johnstone, M, Zimmer, C, Mössner, J, Ruffert, C, Krehan, M, Zapf, C, Njølstad, PR, Johansson, S, Bugert, P, Miyajima, F, Liloglou, T, Brown, LJ, Winn, SA, Davies, K, Latawiec, D, Gunson, BK, Criddle, DN, Pirmohamed, M, Grützmann, R, Michl, P, Greenhalf, W, Molven, A, Sutton, R & Rosendahl, J 2016, 'Length of variable numbers of tandem repeats in the carboxyl ester lipase (CEL) gene may confer susceptibility to alcoholic liver cirrhosis but not alcoholic chronic pancreatitis', PLoS ONE, vol. 11, no. 11, pp. e0165567. https://doi.org/10.1371/journal.pone.0165567

TY - JOUR

T1 - Length of variable numbers of tandem repeats in the carboxyl ester lipase (CEL) gene may confer susceptibility to alcoholic liver cirrhosis but not alcoholic chronic pancreatitis

AU - Fjeld, Karianne

AU - Beer, Sebastian

AU - Johnstone, Marianne

AU - Zimmer, Constantin

AU - Mössner, Joachim

AU - Ruffert, Claudia

AU - Krehan, Mario

AU - Zapf, Christian

AU - Njølstad, Pål Rasmus

AU - Johansson, Stefan

AU - Bugert, Peter

AU - Miyajima, Fabio

AU - Liloglou, Triantafillos

AU - Brown, Laura J

AU - Winn, Simon A

AU - Davies, Kelly

AU - Latawiec, Diane

AU - Gunson, Bridget K

AU - Criddle, David N

AU - Pirmohamed, Munir

AU - Grützmann, Robert

AU - Michl, Patrick

AU - Greenhalf, William

AU - Molven, Anders

AU - Sutton, Robert

AU - Rosendahl, Jonas

PY - 2016/11/1

Y1 - 2016/11/1

N2 - BACKGROUND: Carboxyl-ester lipase (CEL) contributes to fatty acid ethyl ester metabolism, which is implicated in alcoholic pancreatitis. The CEL gene harbours a variable number of tandem repeats (VNTR) region in exon 11. Variation in this VNTR has been linked to monogenic pancreatic disease, while conflicting results were reported for chronic pancreatitis (CP). Here, we aimed to investigate a potential association of CEL VNTR lengths with alcoholic CP.METHODS: Overall, 395 alcoholic CP patients, 218 patients with alcoholic liver cirrhosis (ALC) serving as controls with a comparable amount of alcohol consumed, and 327 healthy controls from Germany and the United Kingdom (UK) were analysed by determination of fragment lengths by capillary electrophoresis. Allele frequencies and genotypes of different VNTR categories were compared between the groups.RESULTS: Twelve repeats were overrepresented in UK ACP patients (P = 0.04) compared to controls, whereas twelve repeats were enriched in German ALC compared to alcoholic CP patients (P = 0.03). Frequencies of CEL VNTR lengths of 14 and 15 repeats differed between German ALC patients and healthy controls (P = 0.03 and 0.008, respectively). However, in the genotype and pooled analysis of VNTR lengths no statistical significant association was depicted. Additionally, the 16-16 genotype as well as 16 repeats were more frequent in UK ALC than in alcoholic CP patients (P = 0.034 and 0.02, respectively). In all other calculations, including pooled German and UK data, allele frequencies and genotype distributions did not differ significantly between patients and controls or between alcoholic CP and ALC.CONCLUSIONS: We did not obtain evidence that CEL VNTR lengths are associated with alcoholic CP. However, our results suggest that CEL VNTR lengths might associate with ALC, a finding that needs to be clarified in larger cohorts.

AB - BACKGROUND: Carboxyl-ester lipase (CEL) contributes to fatty acid ethyl ester metabolism, which is implicated in alcoholic pancreatitis. The CEL gene harbours a variable number of tandem repeats (VNTR) region in exon 11. Variation in this VNTR has been linked to monogenic pancreatic disease, while conflicting results were reported for chronic pancreatitis (CP). Here, we aimed to investigate a potential association of CEL VNTR lengths with alcoholic CP.METHODS: Overall, 395 alcoholic CP patients, 218 patients with alcoholic liver cirrhosis (ALC) serving as controls with a comparable amount of alcohol consumed, and 327 healthy controls from Germany and the United Kingdom (UK) were analysed by determination of fragment lengths by capillary electrophoresis. Allele frequencies and genotypes of different VNTR categories were compared between the groups.RESULTS: Twelve repeats were overrepresented in UK ACP patients (P = 0.04) compared to controls, whereas twelve repeats were enriched in German ALC compared to alcoholic CP patients (P = 0.03). Frequencies of CEL VNTR lengths of 14 and 15 repeats differed between German ALC patients and healthy controls (P = 0.03 and 0.008, respectively). However, in the genotype and pooled analysis of VNTR lengths no statistical significant association was depicted. Additionally, the 16-16 genotype as well as 16 repeats were more frequent in UK ALC than in alcoholic CP patients (P = 0.034 and 0.02, respectively). In all other calculations, including pooled German and UK data, allele frequencies and genotype distributions did not differ significantly between patients and controls or between alcoholic CP and ALC.CONCLUSIONS: We did not obtain evidence that CEL VNTR lengths are associated with alcoholic CP. However, our results suggest that CEL VNTR lengths might associate with ALC, a finding that needs to be clarified in larger cohorts.

U2 - 10.1371/journal.pone.0165567

DO - 10.1371/journal.pone.0165567

M3 - Article

C2 - 27802312

SN - 1932-6203

VL - 11

SP - e0165567

JO - PLoS ONE

JF - PLoS ONE

IS - 11

ER -

Length of variable numbers of tandem repeats in the carboxyl ester lipase (CEL) gene may confer susceptibility to alcoholic liver cirrhosis but not alcoholic chronic pancreatitis

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